Accurate diagnosis and rapid treatment of acute ischemia is extremely important for acute ischemic diseases such as myocardial infarction and cerebral infarction, for which an effective treatment method is not present during the acute stage.
It is known that an extracellular matrix (ECM) plays an important role in the curing process after acute myocardial infarction. Since ECM molecules drastically change between accumulation and decomposition, cardiac muscle is remodeled after myocardial infarction, and it has been reported that a wide variety of biological substances such as protease, its inhibitor, growth factor and the like are involved in the ECM reconstitution. It is known that, in this process, expression of matrix metalloprotease (MMP) is particularly promoted and activated.
In addition, since cardiac muscle remodeling after myocardial infarction is also influenced by the formation and development (angiogenesis) of collateral vessels, the role of angiogenesis growth factor in acute myocardial infarction is also drawing attention. The vascular endothelial growth factor (VEGF) is a vascular endothelial mitogen considered to be involved in angiogenesis. VEGF shows promoted expression within 1 hr from ligation of the coronary artery. In addition, erythropoietin is a hormone enhancing growth of red blood cells, and promotes expression in a hypoxic state.
However, the expression of VEGF and erythropoietin is not induced in a particular organ or organum, and shows time dependency exhibiting increased expression as the ischemic interval grows longer. Thus, it was difficult to determine hypoxic state of a particular tissue by using them as biomarkers, and identification of the cause of transient acute ischemic state (e.g., acute ischemic disease) was also difficult.
ADAMTS (A Disintegrin And Metalloprotease with Thrombospondin motifs) is an MMP found in recent years. While expression of ADAMTS is not observed in normal tissues, it is induced by LPS stimulation, and recognizes a wide range of various substrates than MMP.
In addition, ADAMTS has been reported to not only decompose ECM but also function as an angiogenesis inhibitor. For example, ADAMTS-1 and ADAMTS-8 have been reported to have an antiangiogenesis action (see non-patent document 1), and ADAMTS-1 has been reported to suppress angiogenesis induced by FGF-2 and inhibit angiogenesis induced by VEGF. Furthermore, it is also known that ADAMTS-1 is bound to VEGF and inhibits phosphorylation of its receptor, VEGFR2 (see non-patent document 1).
Based on these findings, the present inventors have made a hypothesis that ADAMTS is involved in acute myocardial infarction, and found in rat myocardial infarction model that ADAMTS-1 is mainly hyperexpressed in vascular endothelial cells and cardiac muscle cells in the area of myocardial infarction and peripheral area thereof (see non-patent documents 2 and 3).
non-patent document 1: J. Biol. Chem., 1999 Aug. 13; 274(33): 23349-23357
non-patent document 2: Connective Tissue, 34, 87 (2002)
non-patent document 3: J. Biochem. 136, 439-446 (2004)